Phase I Trial Characterizing the Pharmacokinetic Profile of N-803, a Chimeric IL-15 Superagonist, in Healthy Volunteers.

The oncotherapeutic promise of IL-15, a potent immunostimulant, is limited by a short serum t 1/2 The fusion protein N-803 is a chimeric IL-15 superagonist that has a >20-fold longer in vivo t 1/2 versus IL-15. This phase 1 study characterized the pharmacokinetic (PK) profile and safety of N-803 after s.c. administration to healthy human volunteers. Volunteers received two doses of N-803, and after each dose, PK and safety were assessed for 9 d. The primary endpoint was the N-803 PK profile, the secondary endpoint was safety, and immune cell levels and immunogenicity were measures of interest. Serum N-803 concentrations peaked 4 h after administration and declined with a t 1/2 of ∼20 h. N-803 did not cause treatment-emergent serious adverse events (AEs) or grade ≥3 AEs. Injection site reactions, chills, and pyrexia were the most common AEs. Administration of N-803 was well tolerated and accompanied by proliferation of NK cells and CD8+ T cells and sustained increases in the number of NK cells. Our results suggest that N-803 administration can potentiate antitumor immunity.

Bringing geography to the community: community-based learning and the geography classroom.

Community-based learning is a pedagogical technique designed to bring students out of the classroom and into their communities. Students typically pair with local nonprofit organizations to complete work which ties into their scholarship. Faculty, students, and community members can all benefit from these partnerships, and university-community relations are strengthened by them. These connections deepen the educational experience and improve student success and retention, and build civic engagement skills that benefit the university community and the student's home community (Strait, Turk, and Nordyke in: JR Strait, K Nordyke (eds), Pedagogy Of Civic Engagement, High-Impact Practices, and e-Service- L Earning, Stylus Publishing, Virginian, 2015; Bednarz in Journal of Geography in Higher Education 32:87-100, 2008; Mohan in Journal of Geography in Higher Education 19:129-142, 1995). Spatial citizenship, while vital to such engagement and to effective community participation, is seldom taught in traditional pedagogy (Kanwischer, Schulze, and Gryl in: Thomas Jekel, Adrijana Car, Josef Strobl, and Gerald Griesebner (eds), Spatial citizenship-dimensions of a curriculum, Wichmann Verlag, Berlin, 2012). Connecting place to pedagogy with spatially-enabled learning helps students investigate complex global concepts at a manageable local scale. Geography is an intrinsic part of scholarship, to varying degrees, and spatial thinking can bring added dimension and value to the educational process (Vogler in: Thomas Jekel, Adrijana Car, Josef Strobl, and Gerald Griesebner (eds), Wichmann Verlag, Berlin, 2012). The intersectionalities which exist within the community, when examined with a spatial lens, are the core of community geography, a praxis-focused method of engaged scholarship (Shannon in Progress in Human Geography, 10.1177/0309132520961468, 2020). Community-based learning is not clearly defined, yet some established models exist. Place-based learning communities move cohorts of students through a curriculum that is centered on local community issues, with the community as both laboratory and lens, and building place attachment (Schweizer, Davis, and Thompson in Environmental Communication 7:42-62, 2013). Service learning, while less clearly defined, typically involves direct work with community organizations, identifying, investigating, and contributing to solutions for local issues (Strait, Turk, and Nordyke in: JR Strait, K Nordyke (eds), Pedagogy Of Civic Engagement, High-Impact Practices, and e-Service- L Earning, Stylus Publishing, Virginian, 2015; Cal Corps Public Service in Designing Community-Based Courses, 1-45, 2015). Built around the concept of place, the added dimension of improved spatial citizenship benefits both community and students. This paper will review community-based learning as practiced through upper-division service learning courses in geography at two universities, and the development of a new course, as methods of engagement with local communities through a spatial lens.

Phase I Trial of N-803, an IL15 Receptor Agonist, with Rituximab in Patients with Indolent Non-Hodgkin Lymphoma.

PURPOSE: N-803 is an IL15 receptor superagonist complex, designed to optimize in vivo persistence and trans-presentation, thereby activating and expanding natural killer (NK) cells and CD8+ T cells. Monoclonal antibodies (mAbs) direct Fc receptor-bearing immune cells, including NK cells, to recognize and eliminate cancer targets. The ability of IL15R agonists to enhance tumor-targeting mAbs in patients has not been reported previously. PATIENTS AND METHODS: Relapsed/refractory patients with indolent non-Hodgkin lymphoma were treated with rituximab and intravenous or subcutaneous N-803 on an open-label, dose-escalation phase I study using a 3+3 design (NCT02384954). Primary endpoint was maximum tolerated dose. Immune correlates were performed using multidimensional analysis via mass cytometry and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) which simultaneously measures protein and single-cell RNA expression. RESULTS: This immunotherapy combination was safe and well tolerated and resulted in durable clinical responses including in rituximab-refractory patients. Subcutaneous N-803 plus rituximab induced sustained proliferation, expansion, and activation of peripheral blood NK cells and CD8 T cells, with increased NK cell and T cells present 8 weeks following last N-803 treatment. CITE-seq revealed a therapy-altered NK cell molecular program, including enhancement of AP-1 transcription factor. Furthermore, the monocyte transcriptional program was remodeled with enhanced MHC expression and antigen-presentation genes. CONCLUSIONS: N-803 combines with mAbs to enhance tumor targeting in patients, and warrants further investigation in combination with immunotherapies.

Phase I Trial of ALT-803, A Novel Recombinant IL15 Complex, in Patients with Advanced Solid Tumors.

Purpose: IL15 induces the activation and proliferation of natural killer (NK) and memory CD8+ T cells and has preclinical antitumor activity. Given the superior activity and favorable kinetics of ALT-803 (IL15N72D:IL15RαSu/IgG1 Fc complex) over recombinant human IL15 (rhIL15) in animal models, we performed this first-in-human phase I trial of ALT-803 in patients with advanced solid tumors.Patients and Methods: Patients with incurable advanced melanoma, renal cell, non-small cell lung, and head and neck cancer were treated with ALT-803 0.3 to 6 µg/kg weekly intravenously or 6 to 20 µg/kg weekly subcutaneously for 4 consecutive weeks, every 6 weeks. Immune correlates included pharmacokinetics, immunogenicity, and lymphocyte expansion and function. Clinical endpoints were toxicity and antitumor activity.Results: Twenty-four patients were enrolled; 11 received intravenous and 13 received subcutaneous ALT-803. Of these patients, nine had melanoma, six renal, three head and neck, and six lung cancer. Although total lymphocyte and CD8+ T-cell expansion were modest, NK cell numbers rose significantly. Neither anti-ALT-803 antibodies nor clinical activity were observed. Overall, ALT-803 was well tolerated, with adverse effects including fatigue and nausea most commonly with intravenous administration, whereas painful injection site wheal was reported most commonly with subcutaneous ALT-803.Conclusions: Subcutaneous ALT-803 produced the expected NK cell expansion and was well tolerated with minimal cytokine toxicities and a strong local inflammatory reaction at injection sites in patients with advanced cancer. These data, together with compelling evidence of synergy in preclinical and clinical studies, provide the rationale for combining ALT-803 with other anticancer agents. Clin Cancer Res; 24(22); 5552-61. ©2018 AACR.

ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial.

BACKGROUND: Immunotherapy with PD-1 or PD-L1 blockade fails to induce a response in about 80% of patients with unselected non-small cell lung cancer (NSCLC), and many of those who do initially respond then develop resistance to treatment. Agonists that target the shared interleukin-2 (IL-2) and IL-15Rßγ pathway have induced complete and durable responses in some cancers, but no studies have been done to assess the safety or efficacy of these agonists in combination with anti-PD-1 immunotherapy. We aimed to define the safety, tolerability, and activity of this drug combination in patients with NSCLC. METHODS: In this non-randomised, open-label, phase 1b trial, we enrolled patients (aged ≥18 years) with previously treated histologically or cytologically confirmed stage IIIB or IV NSCLC from three academic hospitals in the USA. Key eligibility criteria included measurable disease, eligibility to receive anti-PD-1 immunotherapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received the anti-PD-1 monoclonal antibody nivolumab intravenously at 3 mg/kg (then 240 mg when US Food and Drug Administration [FDA]-approved dosing changed) every 14 days (either as new treatment or continued treatment at the time of disease progression) and the IL-15 superagonist ALT-803 subcutaneously once per week on weeks 1-5 of four 6-week cycles for 6 months. ALT-803 was administered at one of four escalating dose concentrations: 6, 10, 15, or 20 µg/kg. The primary endpoint was to define safety and tolerability and to establish a recommended phase 2 dose of ALT-803 in combination with nivolumab. Analyses were per-protocol and included any patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02523469; phase 2 enrolment of patients is ongoing. FINDINGS: Between Jan 18, 2016, and June 28, 2017, 23 patients were enrolled and 21 were treated at four dose levels of ALT-803 in combination with nivolumab. Two patients did not receive treatment because of the development of inter-current illness during enrolment, one patient due to leucopenia and one patient due to pulmonary dysfunction. No dose-limiting toxicities were recorded and the maximum tolerated dose was not reached. The most common adverse events were injection-site reactions (in 19 [90%] of 21 patients) and flu-like symptoms (15 [71%]). The most common grade 3 adverse events, occurring in two patients each, were lymphocytopenia and fatigue. A grade 3 myocardial infarction occurred in one patient. No grade 4 or 5 adverse events were recorded. The recommended phase 2 dose of ALT-803 is 20 µg/kg given once per week subcutaneously in combination with 240 mg intravenous nivolumab every 2 weeks. INTERPRETATION: ALT-803 in combination with nivolumab can be safely administered in an outpatient setting. The promising clinical activity observed with the addition of ALT-803 to the regimen of patients with PD-1 monoclonal antibody relapsed and refractory disease shows evidence of anti-tumour activity for a new class of agents in NSCLC. FUNDING: Altor BioScience (a NantWorks company), National Institutes of Health, and Medical University of South Carolina Hollings Cancer Center.

First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation.

New therapies for patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) are needed. Interleukin 15 (IL-15) is a cytokine that stimulates CD8+ T-cell and natural killer (NK) cell antitumor responses, and we hypothesized this cytokine may augment antileukemia/antilymphoma immunity in vivo. To test this, we performed a first-in-human multicenter phase 1 trial of the IL-15 superagonist complex ALT-803 in patients who relapsed >60 days after allo-HCT. ALT-803 was administered to 33 patients via the IV or subcutaneous (SQ) routes once weekly for 4 doses (dose levels of 1, 3, 6, and 10 µg/kg). ALT-803 was well tolerated, and no dose-limiting toxicities or treatment-emergent graft-versus-host disease requiring systemic therapy was observed in this clinical setting. Adverse events following IV administration included constitutional symptoms temporally related to increased serum IL-6 and interferon-γ. To mitigate these effects, the SQ route was tested. SQ delivery resulted in self-limited injection site rashes infiltrated with lymphocytes without acute constitutional symptoms. Pharmacokinetic analysis revealed prolonged (>96 hour) serum concentrations following SQ, but not IV, injection. ALT-803 stimulated the activation, proliferation, and expansion of NK cells and CD8+ T cells without increasing regulatory T cells. Responses were observed in 19% of evaluable patients, including 1 complete remission lasting 7 months. Thus, ALT-803 is a safe, well-tolerated agent that significantly increased NK and CD8+ T cell numbers and function. This immunostimulatory IL-15 superagonist warrants further investigation to augment antitumor immunity alone and combined with other immunotherapies. This trial was registered at www.clinicaltrials.gov as #NCT01885897.

A multicenter, randomized, open-label, active-comparator trial to determine the efficacy, safety, and pharmacokinetics of intravenous ibuprofen for treatment of fever in hospitalized pediatric patients.

BACKGROUND: Oral antipyretics are commonly used to treat pediatric patients who develop fevers. However, patients presenting to the emergency department or undergoing surgery are frequently unable to tolerate oral antipyretics. Rectal formulations are available; however, this route of administration is unpredictable. The main objectives of this randomized controlled study was to evaluate the efficacy and safety of single or multiple doses of intravenous ibuprofen to acetaminophen (oral or suppository) in pediatric patients with fever and to assess plasma ibuprofen concentrations. METHODS: This multi-center study was conducted in hospitalized patients, ≤ 16 years, with a new onset of fever ≥ 38.3°C. Patients were randomly assigned to receive either 10 mg/kg intravenous ibuprofen or acetaminophen. Study drug was administered at hour 0, and thereafter every 4 h as needed, up to 5 days. The primary outcome was to evaluate the effect of a single dose of intravenous ibuprofen compared to acetaminophen in reducing temperature in the first 2 h after administration. Data were compared using an analysis of variance model for continuous measurements and Cochran-Mantel-Haenszel test of general association for categorical data. A two-sided testing was used and a p-value ≤ 0.05 was considered significant. RESULTS: A total of 103 patients received study medication. Intravenous ibuprofen resulted in a greater reduction in temperature as measured by the area under the change from baseline at 2 h (p = 0.005) and 4 h (<0.001); in a greater reduction in change from baseline temperature compared to treatment with acetaminophen, and it reduced fever throughout a 24 h dosing period. There were no differences in safety parameters or serious adverse events. CONCLUSIONS: A single 10 mg/kg dose of intravenous ibuprofen provided a significant reduction of temperature for febrile pediatric patients compared to those that received 10 mg/kg acetaminophen at 2 h and 4 h post-treatment. A reduction in temperature was also demonstrated over 24 h; however the reduction was not considered statically significant. Intravenous ibuprofen provides an effective option for reducing fever in hospitalized pediatric patients. TRIAL REGISTRATION: The study was registered on ClinicalTrials.gov on 26 October 2009, Study Identifier: NCT01002573.

Dose comparison of conivaptan (Vaprisol®) in patients with euvolemic or hypervolemic hyponatremia--efficacy, safety, and pharmacokinetics.

PURPOSE: This study aimed to evaluate the efficacy, safety, and pharmacokinetics of 20 and 40 mg/day conivaptan (Vaprisol®) in patients with hypervolemic or euvolemic hyponatremia. METHODS: Hyponatremic patients - serum sodium (sNa) ≤130 mEq/L - received either 20 or 40 mg/day of conivaptan for 4 days, following an initial 20 mg loading dose. Efficacy was evaluated by the magnitude and extent of change in sNa. Safety was evaluated by the incidence of adverse events, changes in vital signs and laboratory parameters, rate of sNa correction, and frequency of infusion-site reactions. Pharmacokinetic parameters were also measured. RESULTS: A total of 37 patients received 20 mg/day and 214 patients received 40 mg/day conivaptan. Baseline-adjusted sNa-area under the concentration-time curve increased by an average of 753.8±499.9 mEq·hr/L (20 mg/day) and 689.2±417.3 mEq·hr/L (40 mg/day) over the course of the 4-day treatment period. The majority of patients in both treatment groups achieved a 4 mEq/L increase in sNa over baseline in ~24 hours (82.5%). Average increase in sNa after 4 days was ~10 mEq/L, varying with dosage level and baseline volume status. Treatment success (normal sNa or increase of ≥6 mEq/L) was attained by 70.3% of patients in the 20 mg/day group and 72.0% in the 40 mg/day group. CONCLUSION: Both 20 and 40 mg/day doses of conivaptan are efficacious in increasing sNa over 4 days of treatment with no observed increase in the frequency of adverse events or specific infusion-site reactions using the higher dose. The pharmacokinetic parameters of both doses were similar to what has been reported previously, exhibiting greater-than-dose-proportional plasma concentrations.

An integrated safety analysis of intravenous ibuprofen (Caldolor(®)) in adults.

Intravenous (IV) nonsteroidal anti-inflammatory drugs such as IV ibuprofen are increasingly used as a component of multimodal pain management in the inpatient and outpatient settings. The safety of IV ibuprofen as assessed in ten sponsored clinical studies is presented in this analysis. Overall, 1,752 adult patients have been included in safety and efficacy trials over 11 years; 1,220 of these patients have received IV ibuprofen and 532 received either placebo or comparator medication. The incidence of adverse events (AEs), serious AEs, and changes in vital signs and clinically significant laboratory parameters have been summarized and compared to patients receiving placebo or active comparator drug. Overall, IV ibuprofen has been well tolerated by hospitalized and outpatient patients when administered both prior to surgery and postoperatively as well as for nonsurgical pain or fever. The overall incidence of AEs is lower in patients receiving IV ibuprofen as compared to those receiving placebo in this integrated analysis. Specific analysis of hematological and renal effects showed no increased risk for patients receiving IV ibuprofen. A subset analysis of elderly patients suggests that no dose adjustment is needed in this higher risk population. This integrated safety analysis demonstrates that IV ibuprofen can be safely administered prior to surgery and continued in the postoperative period as a component of multimodal pain management.

A prospective, multicenter, randomized, double-blind trial of IV ibuprofen for treatment of fever and pain in burn patients.

This prospective study evaluated the efficacy and safety of IV ibuprofen for the reduction of fever and treatment of pain in patients with thermal burn injury. A total of 61 patients with second- and/or third-degree thermal burns covering >10% TBSA were randomly assigned in a 2:1 ratio to receive either 800 mg IV ibuprofen or placebo every 6 hours for 120 hours (5 days). Antipyretic medications were restricted during the first 24 hours of the study, but analgesics were allowed throughout. The primary efficacy endpoint was area under the curve for temperature (AUC-T°) within the first 24 hours of treatment. After 24 hours of dosing, there was a significant reduction in temperature in patients who received IV ibuprofen compared with those who received placebo (P = .008). The temperature remained reduced over the entire 120-hour dosing period in the patients who received IV ibuprofen, although the difference beyond 24 hours did not reach statistical significance. Because of enrollment of patients unable to perform self-assessments of pain, an inadequate number of patients were enrolled to detect differences in pain scores. There was no significant difference in the incidence of serious adverse events. Fever was reduced significantly by IV ibuprofen in burn patients over the initial 24-hour dosing period and remained reduced throughout the dosing period. Exposure to the maximum daily recommended dose of 3200 mg (800 mg every 6 hours) for a total of 120 hours (5 days) was well tolerated.

Pharmacokinetics, safety, and tolerability of a rapid infusion of i.v. ibuprofen in healthy adults.

PURPOSE: The pharmacokinetics, safety, and tolerability of a rapid infusion of i.v. ibuprofen in healthy adults were evaluated. Methods In this randomized, double-blind, placebo-controlled, single-dose, crossover study, 12 healthy subjects age 18-65 years were randomized to receive a single dose of either 800 mg i.v. ibuprofen (infused over five to seven minutes) concomitantly with an oral placebo or 800 mg oral ibuprofen with concomitant i.v. placebo (0.9% sodium chloride injection). After a six-day washout period, subjects received the treatment not previously received. Blood samples were taken 1 hour before each dose of study medication was administered and throughout the 12 hours thereafter. Plasma ibuprofen concentrations were determined using validated liquid chromatography-tandem mass spectrometry methods. The frequency and severity of treatment-emergent adverse effects were monitored throughout the study. RESULTS: The maximum plasma concentration (C(max)) of i.v. ibuprofen was approximately twice that of oral ibuprofen, and the (t(max)) of i.v. ibuprofen was 0.11 hour, compared with 1.5 hours for oral ibuprofen. However, the elimination half-life of i.v. and oral ibuprofen did not differ, both of which were approximately 2 hours. Oral ibuprofen was 100% bioavailable; therefore, the area under the concentration-time curve did not differ between i.v. and oral ibuprofen. In addition, i.v. ibuprofen infused over five to seven minutes did not differ in terms of safety or tolerability when compared with oral ibuprofen. CONCLUSION: I.V. ibuprofen, when administered over five to seven minutes in healthy subjects, achieved a higher C(max) and a more-rapid t(max) than did oral ibuprofen and was found to be safe and well tolerated.

A multicenter, randomized, double-blind, placebo-controlled trial of intravenous ibuprofen (i.v.-ibuprofen) in the management of postoperative pain following abdominal hysterectomy.

BACKGROUND: Ibuprofen and other nonsteroidal anti-inflammatory drugs are widely used to block pain and inflammation in a variety of settings. Contrarily, opioid analgesia does not block the inflammatory component of pain and the use of these agents can be accompanied by serious side effects. We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of intravenous ibuprofen (i.v.-ibuprofen) as a postoperative analgesic. METHODS: A total of 319 patients were randomly assigned in a 1:1 ratio to receive 800 i.v.-ibuprofen or placebo every 6 hours; in addition patients had access to morphine at a dose of 1-2 mg every 5 minutes. The primary outcome measure was median morphine consumption within the first 24 hours following surgery. RESULTS: During the first 24 hours of treatment, the median morphine requirement was reduced by 19% (P ≤ 0.001) and resulted in a significant reduction in pain at rest (AUC, 6 to 24 hours and 12 to 24 hours, P < 0.001) and pain with movement (AUC, 6 to 24 hours, P = 0.010 and 12 to 24 hours, P ≤ 0.001) as measured by the visual analog scale (VAS) in patients receiving 800 mg i.v.-ibuprofen compared to placebo. Time to ambulation was significantly faster (P = 0.018) in the i.v.-ibuprofen treated group, as well. Similar treatment-emergent adverse events occurred across both study groups and there was no difference in the overall incidence of these events. CONCLUSION: This study demonstrated that i.v.-ibuprofen is an effective analgesic medication that is safe and well tolerated when administered as an 800 mg dose every 6 hours in patients undergoing total abdominal hysterectomy surgery.

A multi-center, randomized, double-blind placebo-controlled trial of intravenous-ibuprofen (IV-ibuprofen) for treatment of pain in post-operative orthopedic adult patients.

OBJECTIVE: To determine whether pre- and post-operative administration of intravenous ibuprofen (IV-ibuprofen) can significantly decrease pain and morphine use when compared with placebo in adult orthopedic surgical patients. DESIGN: This was a multi-center, randomized, double-blind placebo-controlled trial. SETTING: This study was completed at eight hospitals; six in the United States and two in South Africa. PATIENTS: A total of 185 adult patients undergoing elective orthopedic surgery. INTERVENTIONS: Patients were randomized to receive either 800 mg IV-ibuprofen or placebo every 6 hours, with the first dose administered pre-operatively. Additionally, all patients had access to intravenous morphine for rescue. OUTCOME MEASURES: Efficacy of IV-ibuprofen was demonstrated by measuring the patient's self assessment of pain using a visual analog scale (VAS; assessed with movement and at rest) and a verbal response scale (VRS). Morphine consumption during the post-operative period was also assessed. RESULTS: In the immediate post-operative period, there was a 25.8% reduction in mean area under the curve-VAS assessed with movement (AUC-VASM) in patients receiving IV-ibuprofen (P < 0.001); a 31.8% reduction in mean AUC-VAS assessed at rest (AUC-VASR; P < 0.001) and a 20.2% reduction in mean VRS (P < 0.001) compared to those receiving placebo. Patients receiving IV-ibuprofen used 30.9% less morphine (P < 0.001) compared to those receiving placebo. Similar treatment emergent adverse events occurred in both study groups and there were no significant differences in the incidence of serious adverse events. CONCLUSION: Pre- and post-operative administration of IV-ibuprofen significantly reduced both pain and morphine use in orthopedic surgery patients in this prospective randomized placebo-controlled trial.

A multicenter, randomized, double-blind, placebo-controlled trial of intravenous ibuprofen 400 and 800 mg every 6 hours in the management of postoperative pain.

BACKGROUND: Although opioids are the mainstay of inpatient postoperative pain management, they do not block inflammation. The NSAID ibuprofen has antiinflammatory and analgesic properties, and a multimodal approach may reduce opioid requirements. OBJECTIVE: This study was conducted to assess the effects of intravenously administered ibuprofen 400 and 800 mg q6h in postoperative pain management. METHODS: This multicenter, randomized, double-blind, placebo-controlled trial was conducted in 406 patients scheduled to undergo elective, single-site orthopedic or abdominal surgery. All patients received morphine administered by patient-controlled analgesia pump, or by hospital staff at the request of the patient, after surgery and were randomly assigned in a 1:1:1 ratio to receive ibuprofen 400 mg IV, ibuprofen 800 mg IV, or inactive vehicle (placebo). The first dose of study drug was administered intraoperatively at the initiation of wound closure, then every 6 hours for a total of 8 doses over the first 48 hours of the study. After the initial 8 doses, the protocol allowed for continued administration of IV ibuprofen or placebo every 6 hours, at the discretion of the investigator, for control of postoperative pain for a total of up to 120 hours (5 days). The ibuprofen and placebo were administered while patients had access to morphine throughout the duration of the study. The primary outcome measure was morphine use in the first 24 hours after surgery. Secondary measures were patient self-reports of pain scores at rest and with movement. Pain intensity was measured before (baseline) and at 1, 2, 3, 6, 9, 12, 15, 18, 24, 27, 30, 33, 36, 39, 42, 45, and 48 hours after the first administration of study medication, and then once daily through day 5 if the patient continued to receive study medication. Patients were assessed by study personnel for treatment-emergent adverse events (AEs). RESULTS: A total of 406 patients were enrolled (319 women, 87 men; mean [SD] age, 45 [12] years; weight, 83.8 [19.1] kg; ibuprofen 400 mg IV, 134 patients; ibuprofen 800 mg IV, 138; and placebo, 134). In the intent-to-treat population, median morphine use was significantly reduced during the first 24 hours after administration of the study drug in patients who received ibuprofen 800 mg IV q6h (by 22% vs placebo; P = 0.030). The use of ibuprofen 800 mg IV q6h was associated with significant reductions in pain at rest and with movement across 3 time periods (1-24, 6-24, 12- 24 hours) compared with placebo. Ibuprofen 400 mg IV q6h was associated with significant reductions in pain at rest and with movement during the 6- to 24-hour and 12- to 24-hour time periods compared with placebo. The prevalences of AEs and abnormalities in laboratory measurements were not significantly different between patients who received IV ibuprofen and those who received placebo. Treatment-emergent AEs were reported in 368 of 406 patients (91%). With respect to the number of patients who experienced serious AEs, the differences in the 400-mg IV ibuprofen group (118/134 [88%]) and the 800-mg IV ibuprofen group (124/138 [90%]) compared with the placebo group (126/134 [94%]) were not statistically significant. There were significant reductions in the proportions of patients who experienced gastrointestinal disorders in the 400- and 800-mg IV ibuprofen groups compared with the placebo group (99/134 [74%] and 98/138 [71%], respectively, vs 113/134 [84%]; P = 0.05 and P = 0.009). There were significant reductions in the numbers of patients experiencing pyrexia in the 400- and 800-mg IV ibuprofen groups compared with the placebo group (9/134 [7%] and 10/138 [7%] vs 23/134 [17%]; P = 0.013 and P = 0.015). Dizziness occurred in a significantly greater proportion of patients in the ibuprofen 800-mg q6h group compared with the placebo group (P = 0.011). CONCLUSIONS: In these patients undergoing postoperative pain management, ibuprofen 800 mg IV q6h was associated with significant reductions in morphine use and pain at rest and with movement compared with placebo. Ibuprofen IV was not associated with significant increases in AEs compared with placebo, with the exception of dizziness with the 800-mg dose. These findings suggest that ibuprofen 800 mg IV q6h was effective for postoperative pain management and was generally well tolerated. ClinicalTrials.gov identifier: NCT00225732.